Catalytic titanium (IV) oxide, mediated geminal symmetric dialkylation of carboxamides

ABSTRACT

The present invention relates to a process preparing compounds of the general formula (I)  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are defined herein.

[0001] The present invention relates to a process for the symmetricdisubstitution of carboxamides at the geminal carbonyl C atom usingGrignard reagents in the presence of titanium dioxide, and to thecompounds, prepared by this process, of the general formula (I)

[0002] in which

[0003] R¹, R² and R³ independently of one another are H, A, Ar,—Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ or R¹ and R² or R¹ and R³ or R⁸and R⁹ can be attached to one another and together form a cyclic ringhaving 3 to 8 C atoms which optionally contains, in addition tonitrogen, at least one further heteroatom selected from the groupconsisting of —S—, —O— and —NR⁶—,

[0004] R⁴ is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹, in which R⁸and R⁹ are as defined above or R⁸ and R⁹ or two radicals R⁴ can beattached to one another and together form a cyclic ring having 3 to 8 Catoms which can optionally contain, in addition to one nitrogen atom, atleast one heteroatom selected from the group consisting of —S—, —O— and—NR⁶—,

[0005] R⁶, R⁷, R⁸ and R⁹ independently of one another are A or Ar,

[0006] A is a straight-chain or branched alkyl radical having from 1 to10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10C atoms, or a straight-chain or branched alkynyl radical having 2-10 Catoms or a substituted or unsubstituted cycloalkyl radical having 3-8 Catoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 Catoms, and

[0007] Ar is a substituted or unsubstituted aryl radical having 6-20 Catoms.

[0008] In addition to monoalkylation, geminal dialkylations usingvarious titanium reagents have been included in studies ontitanium-mediated alkylation of carbonyl functions. The geminal dimethylstructure, which is frequently found as a component in terpenes andsteroids, is particularly interesting here. It has been found that alarge number of ketones can be methylated with the aid of (CH₃)₂TiCl₂(M. T. Reetz, J. Westermann, R. Steinbach, J. Chem. Soc., Chem. Commun.(1981) 237; M. T. Reetz, J. Westerman, S. H. Kyung, Chem. Ber. (1985)118, 1050). However, hitherto, no studies on the transfer of other alkylbuilding blocks with the aid of various titanium reagents are known.

[0009] Geminal symmetric dialkylations of amides have been known for along time, on account of their reactions with Grignard reagents (F.Kuffner, S. Sattler-Dornbach, W. Seifried, Mh. Chem. (1962) 93, 469).

[0010] Hitherto, geminal dimethylations giving high yields have onlybeen reported for pure ketones or aldehydes, the reactions beingtitanium-mediated alkylations. To this end, the reagents ZnMe₂ or AlMe₃are required for synthesising the required organotitanium compoundTiMe₂Cl₂, since ethereal solutions of MeMgCl/TiCl₄ only result in asimple addition of the methyl group to keto groups (M. T. Reetz, J.Westermann, R. Steinbach, J. Chem. Soc., Chem. Commun. (1981) 237; M. T.Reetz, J. Westerman, S. H. Kyung, Chem. Ber. (1985) 118, 1050).

[0011] In the hitherto known symmetric dialkylations of amides which arecarried out with the aid of a Grignard reagent, the products are in mostcases only obtained as byproducts. The yields that are obtained are inthe range of a few percent, up to at most about 50%. TABLE 1 AmideGrignard Yield Lit.

11% M. Busch, M. Fleischmann, Chem. Ber. (1910), 43, 2553

53% R. Lukes, J. Langthaler, Collect Czech. Chem. Commun. (1959), 24,110

30% R. Lukes, J. Langthaler, Collect Czech. Chem. Commun. (1959), 24,110

41% R. Lukes, K. Smolek, Collect Czech. Chem. Commun. (1939), 11, 506

[0012] Accordingly, it is the object of the present invention to providean inexpensive process which is easy to carry out and gives, from amidesof the general formula (II)

[0013] in which R¹, R² and R³ have the meanings given above, compoundsof the general formula (I) given above which are substitutedsymmetrically at the geminal carbonyl C atom, in high yield.

[0014] This object is achieved by a process for preparing compounds ofthe general formula (I)

[0015] in which

[0016] R¹, R² and R³ independently of one another are H, A, Ar,—Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ or R¹ and R² or R¹ and R³ or R⁸and R⁹ can be attached to one another and together form a cyclic ringhaving 3 to 8 C atoms which optionally contains, in addition tonitrogen, at least one further heteroatom selected from the groupconsisting of —S—, —O— and —NR⁶—,

[0017] R⁴ is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹, in which R⁸and R⁹ are as defined above or R⁸ and R⁹ or two radicals R⁴ can beattached to one another and together form a cyclic ring having 3 to 8 Catoms which can optionally contain, in addition to one nitrogen atom, atleast one heteroatom selected from the group consisting of —S—, —O— and—NR⁶—,

[0018] R⁶, R⁷, R⁸ and R⁹ independently of one another are A or Ar,

[0019] A is a straight-chain or branched alkyl radical having from 1 to10 C atoms, a straight-chain or branched alkenyl radical having 2 to 10C atoms, or a straight-chain or branched alkynyl radical having 2-10 Catoms or a substituted or unsubstituted cycloalkyl radical having 3-8 Catoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 Catoms, and

[0020] Ar is a substituted or unsubstituted aryl radical having 6-20 Catoms,

[0021] from compounds of the formula (II)

[0022] in which R¹, R² and R³ have the meanings given above for formula(I), by reaction with a nucleophilic reagent of the general formula(IIIa) or a nucleophilic reagent of the general formula (IIIb)

Z-R⁴  (IIIa)

Z-R⁴-R⁴-Z  (IIIb)

[0023] in which

[0024] R⁴ has the meaning given for the formula (I), and

[0025] Z is Li or MgX where

[0026] X is Hal and

[0027] Hal is Cl, Br or I,

[0028] where the latter is generated in situ or added directly.

[0029] According to the invention, the process is carried out in thepresence of catalytic amounts of a metal oxide selected from the groupconsisting of titanium dioxide, zirconium dioxide and hafnium dioxide.

[0030] The present invention also provides a corresponding process whichis carried out in the presence of a cocatalyst. Accordingly, the presentinvention includes a process which is carried out using metalisopropoxides and alkylsilyl halides as cocatalysts; i.e. metalisopropoxides of the general formula (IV) and alkylsilyl halides of thegeneral formula (V)

M′^((s+))(O-isopropyl)_(s)  (IV)

R₃SiX  (V)

[0031] or of the general formula (VI)

R₀—(X)_(m)—Si—Y—(Si)_(p)—(X)_(q)—R₀  (VI)

[0032] in which

[0033] M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,

[0034] s is an integer from 1 to 4 and is the oxidation state of themetal,

[0035] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

[0036] X is F, Cl, Br, CN,

[0037] m is 0, 1,

[0038] n is 1 to 10,

[0039] o is 0, 2, 3,

[0040] p is 0, 1 and

[0041] q is 0, 1,

[0042] with the proviso that o=3 and Y≠(CH₂)_(n) if m=0.

[0043] Thus, the invention also provides a process, which ischaracterized in that

[0044] a) a carboxamide of the general formula (II), 1-15 mol %, basedon the carboxamide, of a metal dioxide selected from the groupconsisting of titanium dioxide, zirconium dioxide and hafnium dioxideand, if appropriate, a cocatalyst are initially charged at roomtemperature under an atmosphere of inert gas in a solvent selected fromthe group consisting of toluene, THF, n-hexane, benzene and diethylether,

[0045] b) a solution comprising a nucleophilic reagent of the generalformula (IIIa) or (IIIb) is added dropwise and

[0046] c) the mixture is allowed to react with stirring and, after thereaction has ended, worked up in a customary manner,

[0047] or in that, if Z=MgX,

[0048] a′) magnesium turnings, a carboxamide of the general formula(II), 1-15 mol %, based on the carboxamide, of a metal oxide selectedfrom the group consisting of titanium dioxide, zirconium dioxide andhafnium dioxide are initially charged at room temperature under anatmosphere of inert gas in a solvent selected from the group consistingof toluene, THF, n-hexane, benzene and diethyl ether,

[0049] b′) an alkyl halide, dissolved in a solvent selected from thegroup consisting of toluene, THF, n-hexane, benzene and diethyl ether,and of the general formula (IIIa′) or (IIIb′)

X—R⁴  (IIIa′)

or

X—R⁴—R⁴—X  (IIIb′)

[0050] in which R⁴ and X have the meanings given for the formula (I), isadded dropwise,

[0051] c′) the mixture is allowed to react with stirring and, after thereaction has ended, worked up in a customary manner.

[0052] Experiments have shown that, using a nucleophilic reagent of thegeneral formula (IIIa) or (IIIb), which may be a Grignard reagent andwhich may either be generated in situ or added as such to the reactionmixture, it is possible to convert carboxamides of the general formula(II) in the presence of catalytic amounts of titanium dioxide, zirconiumdioxide or hafnium dioxide in a simple manner into symmetricallysubstituted compounds of the general formula (I).

[0053] According to the invention, using the process described herein,it is possible to convert, with good yields, carboxamides of the generalformula (II) in which R¹, R² and R³ independently of one another canhave the following meanings:

[0054] H or

[0055] A i.e. branched or unbranched alkyl having 1-10 C atoms, such asmethyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkylhaving 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and corresponding methyl- orethyl-substituted cycloalkyl groups, or mono- or polyunsaturatedcycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, orbranched or unbranched alkenyl having 2 to 10 C atoms, such as allyl,vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2to 10 C atoms, such as ethynyl, propynyl, or

[0056] aryl having 6 to 20 C atoms which is either unsubstituted ormono- or polysubstituted, such as phenyl, naphthyl, anthryl,phenanthryl, mono- or polysubstituted by substituents selected from thegroup consisting of NO₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA, where Acan have the meanings given above, can be mono-, poly-, or fullyhalogenated, preferably fluorinated, or

[0057] aralkenyl or aralkynyl, where the aryl, alkenyl and alkynylgroups can in each case have the given meanings, such as, for example,in phenylethynyl.

[0058] Good yields are in particular also obtained using carboxamides inwhich R¹ and R² or R¹ and R³ together form a cyclic ring having 3-8 Catoms which, in addition to nitrogen, contains further heteroatoms, suchas —S—, —O— or —NR⁶—. Particular preference is given here to compoundsin which R¹ and R² or R¹ and R³ form a simple cyclic ring which includesthe nitrogen of the carboxamide or in which R¹ and R² or R¹ and R³ forma cyclic ring which contains, as further heteroatom, an oxygen atom.

[0059] Thus, high yields are obtained in this manner when the startingmaterials used are compounds such as, for example,

[0060] The nucleophilic reagent used can be a Grignard reagent or anorganolithium compound of the general formulae (IIIa) or (IIIb), inwhich the radical

[0061] R⁴ is preferably an alkyl radical having 1 to 10 C atoms, such asmethyl, ethyl, n- or isopropyl, n-, sec- or t-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl and suitable isomers thereof, or cycloalkylhaving 3-8 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or orethyl-substituted cycloalkyl groups or mono- or polyunsaturatedcycloalkyl groups, such as cyclopentenyl or cyclopentadienyl, orbranched or unbranched alkenyl having 2 to 10 C atoms, such as allyl,vinyl, isopropenyl, propenyl, or branched or unbranched alkynyl having 2to 10 C atoms, such as ethynyl, propynyl, or

[0062] is an aryl radical having 6 to 20 C atoms which is eitherunsubstituted or mono- or polysubstituted, such as phenyl, napthyl,anthryl, phenanthryl, mono- or polysubstituted by substituents selectedfrom the group consisting of NO₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA,where A can have the meanings given above, can be mono-, poly- or fullyhalogenated, preferably fluorinated, or

[0063] is an aralkyl radical having 7 to 20 C atoms, such as benzyl,optionally mono- or polysubstituted by substituents selected from thegroup consisting of NO₂, F, Cl, Br, NH₂, NHA, NA₂, OH and OA, where Acan have the meanings given above, can be mono-, poly- or fullyhalogenated, preferably fluorinated,

[0064] is an aralkenyl or aralkynyl radical, where the aryl, alkenyl andalkynyl group can in each case have the given meanings, such as, forexample, in phenylethynyl.

[0065] Furthermore, the radicals R⁴ in the general formula (IIIa) or(IIIb) can be —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹, in which R⁶, R⁷,R⁸ and R⁹ independently of one another can have the abovementionedmeanings or R⁸ and R⁹ are attached to one another and together form acyclic ring having 3 to 8 C atoms which may optionally, in addition to anitrogen atom, contain at least one heteroatom selected from the groupconsisting of —S—, —O— and —NR⁶—; or

[0066] two radicals R⁴ in the general formula (IIIb) can be an alkylhaving 2-7 C atoms, so that, in the reaction according to the invention,a compound of the general formula (I) is formed in which two radicals R⁴form a cyclic ring having 3 to 8 atoms.

[0067] Particularly preferably, R⁴ has the meaning of an alkyl radical,such as, for example, methyl, ethyl, n- or isopropyl, n-, sec- ort-butyl, pentyl, hexyl, or of a cycloalkyl radical, such as, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or of an arylradical, such as, for example, phenyl, or of an aralkyl radical, suchas, for example, benzyl.

[0068] The radical Z in the general formulae (IIIa) and (IIIb)preferably represents a radical MgX where X is Cl or Br, or the radicalZ is lithium.

[0069] Particular preference according to the invention is given tousing Grignard compounds such as: methylmagnesium bromide,ethylmagnesium bromide, n- or isopropylmagnesium bromide, iso-, sec- ortert-butylmagnesium bromide, n-hexylmagnesium bromide,cyclohexylmagnesium chloride, allylmagnesium bromide, vinylmagnesiumbromide, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride,phenylmagnesium bromide, benzylmagnesium chloride, for the reaction.

[0070] Furthermore, it was found that only if a cocatalyst is added, thegeminal symmetric dialkylation reactions according to the inventionstart even at room temperature and result in the complete conversion ofthe starting materials in a relatively short reaction time.

[0071] Suitable cocatalysts for this reaction are metal isopropoxidesand alkylsilyl halides. Particularly suitable are metal isopropoxides ofthe general formula (IV) and alkylsilyl halides of the general formula(V)

M′^((s+))(O-isopropyl)_(s)  (IV)

R₃SiX  (V)

[0072] or of the general formula (VI)

R₀—(X)_(m)—Si—Y—(Si)_(p)—(X)_(q)—R₀  (VII)

[0073] in which

[0074] M′ is Al, Ca, Na, K, Si or Mg, preferably Mg or Na,

[0075] s is an integer from 1 to 4 and is the oxidation state of themetal,

[0076] R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms,

[0077] X is F, Cl, Br, CN,

[0078] m is 0, 1,

[0079] n is 1 to 10,

[0080] o is 0, 2, 3,

[0081] p is 0, 1 and

[0082] q is 0, 1,

[0083] with the proviso that o=3 and Y≠(CH₂)_(n) if m=0.

[0084] Preference is given to using metal isopropoxides in which s is aninteger from 1 to 4 and is the oxidation state of the metal and M′ isAl, Ca, Na, K, Si or Mg. Particular preference is given to Mg or Na.

[0085] Preference is given to using alkylsilyl halides in which R isalkyl having 1 to 6 C atoms. Particular preference is given to those inwhich R is alkyl having 1 to 3 C atoms and X is chlorine.

[0086] Particularly suitable cocatalysts are, inter alia, the followingsilicon compounds:

[0087] (CH₃)₃SiCl

[0088] (CH₃)₂ClSi(CH₂)₂SiCl(CH₃)₂

[0089] (CH₃)₂ClSi(CH₂)₃CN

[0090] [(CH₃)₃Si]₂O

[0091] [(CH₃)₃Si]₂NH and

[0092] [(CH₃)₃Si]₂.

[0093] It has been found that the addition of from 0.7 to 1.2 mol, inparticular from 0.9 and 1.1 mol, of a cocatalyst based on one mol ofstarting material leads to improved results such as, for example, higheryields, lower reaction temperature or shorter reaction times.

[0094] As can be demonstrated using examples, under favourableconditions a complete conversion of the carboxamide according to thegeneral equation (Eq. 1) has taken place after just one hour:

[0095] For carrying out the process according to the invention, thecatalyst used can be a commercial metal dioxide selected from the groupconsisting of titanium dioxide, zirconium dioxide and hafnium dioxide.Preference is given to using pulverulent titanium(IV) dioxide. In thesimplest case, this can be of technical grade. To ensure simple removalafter the reaction has ended, it is advantageous to choose a qualitywhich is not too fine. The metal dioxide, preferably titanium dioxide,which is pre-dried by heating, is employed as a suspension in a suitablepre-dried solvent. Suitable solvents are, for example aliphatic oraromatic hydrocarbons or ethers. Preference is given to using solventsselected from the group consisting of toluene, THF, n-hexane, benzeneand diethyl ether, which are dried prior to the reaction by methodsknown to the person skilled in the art. Drying can be carried out withthe aid of magnesium sulphate, calcium chloride, sodium, potassiumhydroxide or by other methods.

[0096] A preferred embodiment of the process according to the inventioncomprises initially charging the titanium dioxide used as catalyst in anamount of from 1 to 15, preferably 1.5 to 14, in particular 2 to 10 andvery particularly preferably from 3 to 6 mol %, based on one mol of theamide used as starting material, in the form of a suspension adjusted toa temperature of from 10 to 30° C., preferably 15-25° C., particularlypreferably to a temperature of about 20° C. Under an atmosphere of inertgas (nitrogen or argon), the starting material, either as such in liquidform or dissolved in a solvent selected from the group consisting oftoluene, THF, n-hexane, benzene and diethyl ether, is slowly addeddropwise with stirring. An amount of cocatalyst which corresponds to theamount to be reacted is then added dropwise, if required likewise in asolvent. The reaction mixture obtained is stirred for a short period,i.e. for a few minutes, at a constant temperature. Such an excess of thenucleophilic reagent of the general formula (IIIa) or (IIIb), inparticular a Grignard reagent, is then slowly added to the resultingreaction mixture that substitution of the geminal carbonyl C atom by twoidentical substituents, i.e. a symmetric substitution of the geminalcarbonyl C atom, can take place. The addition of a nucleophilic reagentaccording to the invention prepared by methods generally known to theperson skilled in the art should take place at such a rate that thetemperature of the reaction mixture does not exceed 50° C. It isadvantageous to carry out the addition of the nucleophilic reagent, i.e.of the Grignard reagent or the lithium compound, with efficient mixing,preferably vigorous stirring. To shift the reaction equilibrium to theside of the desired symmetrically substituted product, the nucleophilicreagent used, preferably a Grignard reagent, is added in an amount offrom 2.1 to 3 mol per mole of starting material that participates in thereaction. Preference is given to adding the Grignard reagent in anamount of from 2.2 to 2.6 mol, based on 1 mol of starting material. If anucleophilic reagent or Grignard reagent of the general formula (IIIb)is used, only equimolar amounts, based on the starting material, areadded to the reaction solution, corresponding to twice the number ofreactive groups.

[0097] After the addition of the Grignard reagent has ended, thereaction mixture is stirred for some time at a constant temperature,until the reaction is brought to completion.

[0098] Another variant of the process according to the inventioncomprises preparing the Grignard reagent in situ by reacting magnesiumwith a compound of the general formula (IIIa′) or (IIIb′) in which R⁴and X have the meanings given above. In the in situ preparation of theGrignard compounds, the amount of magnesium is preferably 2 to 5 timesthe molar amount, preferably 2.8 to 3.2 times the molar amount, based onthe compounds of the general formula (II) used as starting material, andthe amount of the compound of the general formula (IIIa′) or (IIIb′) is2 to 3.8 times the molar amount, preferably 2.2 to 2.6 times the molaramount, based on the compound of the general formula (II).

[0099] Thus, by the synthesis according to the invention it is possibleto prepare symmetrically substituted amino compounds of the generalformula (I) with good or satisfactory yields within adequate reactiontimes. In an advantageous manner, it is possible, by adding one of thecatalysts in combination with one of the cocatalyst compounds describedof the general formulae (IV), (V) or (VI), to reduce the reaction timesconsiderably, in the most favourable case to one hour, without thisresulting in a reduction in the yields obtained.

[0100] Thus, the present invention also provides the use of a catalystsystem comprising a metal dioxide selected from the group consisting oftitanium dioxide, zirconium dioxide and hafnium dioxide as catalyst anda compound of the general formulae (IV), (V) or (VI) with the meaningsgiven above, and the use of this catalyst system for preparing thesymmetrically substituted compounds of the general formula (I).

[0101] For example, 5 mmol of starting material are, at 20° C. and underan atmosphere of inert gas, added dropwise with stirring to a suspensionof 3 mol % of titanium (IV) oxide in 40 ml of dried tetrahydrofuran. 5mmol of cocatalyst, likewise taken up in dried tetrahydrofuran, areadded slowly with stirring to this mixture. The mixture is stirred at20° C. for 5 minutes, and 12 mmol of Grignard reagent are then added atsuch a rate that the temperature of the reaction mixture does not exceed50° C. Stirring is continued for one hour, until the reaction has goneto completion.

[0102] After the reaction according to the invention, work-up of thereaction mixture can be carried out in a manner known to the personskilled in the art.

[0103] Here, the products can be precipitated as salts using solutionsof hydrochloric acid, for example a 1 molar ethereal solution ofhydrochloric acid, and be filtered off and, if required, purified byrecrystallization.

[0104] To remove the Lewis acid, it is possible, for example, to add asuitable amount of saturated ammonium chloride solution and water,followed by further vigorous stirring for a plurality of hours (1-3hours). The resulting precipitate is separated off and washed with alittle ether, preferably diethyl ether. The filtrate is made alkaline(pH>10) by addition of a suitable base, such as an NaOH, KOH, sodiumcarbonate or potassium carbonate solution, preferably sodium hydroxidesolution. The phases that are formed are then separated, and the aqueousphase is extracted repeatedly (for example in the special case givenabove three times with in each case 30 ml) with diethyl ether. Thecombined organic phases are washed with (for example 15 ml of) saturatedsodium chloride solution and can be dried over potassium carbonate,magnesium sulphate or sodium sulphate and filtered.

[0105] The products can be purified by various routes using methodsknown to the person skilled in the art, such as, for example, in thefollowing manner:

[0106] 1. They are precipitated as hydrochlorides using 1 M etherealhydrochloric acid solution and filtered off (the resulting product is,if required, purified by recrystallization).

[0107] 2. The organic phase is extracted repeatedly with a 0.5 M acidsolution, preferably an aqueous hydrochloric acid solution. The extractobtained is adjusted to pH>10 using bases, preferably 2 M aqueous sodiumhydroxide solution, and extracted at least once, preferably repeatedly,with diethyl ether. The resulting organic phases, which contain thereaction product, can be dried, if appropriate, over potassiumcarbonate, magnesium sulphate or sodium sulphate and be freed from theorganic solvent under reduced pressure.

[0108] 3. Furthermore, it is possible to isolate the reaction product byremoving the organic solvent under reduced pressure and separating theresidue that remains by column chromatography, to isolate the reactionproduct.

[0109] In the general description of the process procedure given above,the Grignard reagents can also be replaced by the corresponding lithiumcompounds. The corresponding lithium compounds, like the Grignardreagents, can be prepared by methods generally known to the personskilled in the art, and they can be reacted according to the inventionin the same manner as described above.

[0110] The compounds of the general formula (I) prepared according tothe invention can be used, for example, as intermediates in thepreparation of sulphur- or selenium-containing amines for the chiralcatalysis of diethyl zinc syntheses (literature: Werth, Thomas;Tetrahydron Lett. 36; 1995, 7849-7852, Werth, Thomas et al. Helv. Chim.Acta 79, 1996, 1957-1966).

[0111] To illustrate and better understand the present invention,examples are given below. However, owing to the general validity of thedescribed principle of the invention, they are not meant to reduce thescope of the present application to just these examples.

EXAMPLES Titanium(IV)-oxide-induced Symmetric Dialkylation ofCarboxamides Using Grignard Reagents

[0112] According to the reaction shown in Equation 1, the followingreactions were carried out using one equivalent of (CH₃)₃SiCl ascocatalyst: TABLE 2 TiO₂-induced reaction of carboxamide with R₄MgX

Reaction Amide Product Yield R⁴MgX conditions

95%^([6]) PhMgBr 1 h/RT/ 3 mol % TiO₂

49%^([6]) Cyclopen tyl-MgCl 1 h/RT/ 13 mol % TiO₂

94%^([6]) n-Hexyl-MgBr 1 h/RT/ 13 mol % TiO₂

1. A process for preparing compounds of the general formula (I)

in which R¹, R² and R³ independently of one another are H, A, Ar,—Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ or R¹ and R² or R¹ and R³ or R⁸and R⁹ can be attached to one another and together form a cyclic ringhaving 3 to 8 C atoms which optionally contains, in addition tonitrogen, at least one further heteroatom selected from the groupconsisting of —S—, —O— and —NR⁶—, R⁴ is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷,—OR⁷, —NR⁸R⁹ in which R⁸ and R⁹ are as defined above or R⁸ and R⁹ or tworadicals R⁴ can be attached to one another and together form a cyclicring having 3 C atoms, R⁶, R⁷, R⁸ and R⁹ independently of one anotherare A or Ar, A is a straight-chain or branched alkyl radical having from1 to 10 C atoms, a straight-chain or branched alkenyl radical having 2to 10 C atoms, or a straight-chain or branched alkynyl radical having2-10 C atoms or a substituted or unsubstituted cycloalkyl radical having3-8 C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8C atoms, and Ar is a substituted or unsubstituted aryl radical having6-20 C atoms, characterized in that a compound of the general formula(II)

in which R¹, R² and R³ have the meanings given above for the formula (I)is reacted with a reagent of the general formula (IIIa) or anucleophilic reagent of the general formula (IIIb)Z-R⁴  (IIIa)Z-R⁴—R⁴-Z  (IIIb) in which R⁴ has the meaning given for theformula (I), and Z is Li or MgX where X is Hal and Hal is Cl, Br or I,which is/are generated in situ or added directly, and the process iscarried out in the presence of catalytic amounts of a metal dioxideselected from the group consisting of titanium dioxide, zirconiumdioxide and hafnium dioxide.
 2. A process according to claim 1,characterized in that it is carried out in the presence of a cocatalyst.3. A process according to claim 1, characterized in that it is carriedout in the presence of a metal isopropoxide or an alkylsilyl halidecocatalyst.
 4. A process according to claim 2, characterized in that thecocatalyst used is a metal isopropoxide of the general formula (IV) oran alkylsilyl halide of the general formula (V) M′^((s+))(O-isopropyl)_(s)  (IV)R₃SiX  (V) in which M′ is Al, Ca, Na, K, Si orMg, s is an integer from 1 to 4 and is the oxidation state of the metal,R is alkyl having 1 to 10 C atoms or aryl having 6 to 20 C atoms, X isF, Cl, Br, or CN.
 5. A process according to claim 1, characterized inthat the catalyst used is titanium dioxide.
 6. A process according toclaim 1, characterized in that a) a carboxamide of the general formula(II), 1-15 mol %, based on the carboxamide, of a metal dioxide selectedfrom the group consisting of titanium dioxide, zirconium dioxide andhafnium dioxide and, if appropriate, the cocatalyst are initiallycharged at 10-30° C. under an atmosphere of inert gas in a solventselected from the group consisting of toluene, THF, n-hexane, benzeneand diethyl ether, b) a solution comprising a nucleophilic reagent ofthe general formula (IIIa) or (IIIb) in which R⁴ is A, Ar, —Si(R⁶)₃,—Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ in which R⁸ and R⁹ are as defined above orR⁸ and R⁹ or two radicals R⁴ can be attached to one another and togetherform a cyclic ring having 3 C atoms, R⁶, R⁷, R⁸ and R⁹ independently ofone another are A or Ar, A is a straight-chain or branched alkyl radicalhaving from 1 to 10 C atoms, a straight-chain or branched alkenylradical having 2 to 10 C atoms, or a straight-chain or branched alkynylradical having 2-10 C atoms or a substituted or unsubstituted cycloalkylradical having 3-8 C atoms, or a mono- or polyunsaturated cycloalkylradical having 3-8 C atoms, and Ar is a substituted or unsubstitutedaryl radical having 6-20 C atoms, Z is Li or MgX where X is Hal and Halis Cl, Br or I, is added dropwise and c) the mixture is allowed to reactwith stirring and, after the reaction has ended, worked up in acustomary manner, or in that, if Z=MgX, a′) magnesium turnings, acarboxamide of the general formula (II), 1-15 mol %, based on thecarboxamide, of a metal dioxide selected from the group consisting oftitanium dioxide, zirconium dioxide and hafnium dioxide and, ifappropriate, the cocatalyst are initially charged at 10-30° C. under anatmosphere of inert gas in a solvent selected from the group consistingof toluene, THF, n-hexane, benzene and diethyl ether, b′) an alkylhalide, dissolved in a solvent selected from the group consisting oftoluene, THF, n-hexane, benzene and diethyl ether, and of the generalformula (IIIa′) of (IIIb′) X—R⁴  (IIIa′)orX—R⁴—R⁴—X  (IIIb′) in which R⁴is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ in which R⁸ and R⁹ areas defined above or R⁸ and R⁹ or two radicals R⁴ can be attached to oneanother and together form a cyclic ring having 3 C atoms, R⁶, R⁷, R⁸ andR⁹ independently of one another are A or Ar, A is a straight-chain orbranched alkyl radical having from 1 to 10 C atoms, a straight-chain orbranched alkenyl radical having 2 to 10 C atoms, or a straight-chain orbranched alkynyl radical having 2-10 C atoms or a substituted orunsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- orpolyunsaturated cycloalkyl radical having 3-8 C atoms, and Ar is asubstituted or unsubstituted aryl radical having 6-20 C atoms, X is Cl,Br, or I; is added dropwise, c′) the mixture is allowed to react withstirring and, after the reaction had ended, worked up in a customarymanner.
 7. A process according to claim 6, characterized in that theprocess step a) or a′) is carried out at a temperature of 15-25° C.
 8. Aprocess according to claim 6, characterized in that the process step a)or a′) is carried out at room temperature.
 9. A process according toclaim 1, characterized in that the nucleophilic reagent used is alithium compound of the general formula (IIIa) or (IIIb) in which R⁴ isA, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ in which R⁸ and R⁹ are asdefined above or R⁸ and R⁹ or two radicals R⁴ can be attached to oneanother and together form a cyclic ring having 3 C atoms, R⁶, R⁷, R⁸ andR⁹ independently of one another are A or Ar, A is a straight-chain orbranched alkyl radical having from 1 to 10 C atoms, a straight-chain orbranched alkenyl radical having 2 to 10 C atoms, or a straight-chain orbranched alkynyl radical having 2-10 C atoms or a substituted orunsubstituted cycloalkyl radical having 3-8 C atoms, or a mono- orpolyunsaturated cycloalkyl radical having 3-8 C atoms, and Ar is asubstituted or unsubstituted aryl radical having 6-20 C atoms.
 10. Aprocess according claim 1, characterized in that the compound that thenucleophilic reagent used is a compound of the general formula (IIIa) or(IIIb) in which R⁴ is methyl, ethyl, n- or isopropyl, iso-, sec- ortert-butyl, n-hexyl, cyclopentyl, cyclohexyl, allyl, vinyl, phenyl orbenzyl.
 11. A process according to claim 1, characterized in that thecompound that is reacted is a compound of the general formula (II) inwhich R¹, R² and R³ independently of one another are H, methyl, ethyl,n- or isopropyl, iso-, sec- or tert-butyl, n-hexyl, phenyl or benzyl.12. A process for preparing compounds of the general formula (I)

in which R¹, R² and R³ independently of one another are H, A, Ar,—Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷, —OR⁷, —NR⁸R⁹ or R¹ and R² or R¹ and R³ or R⁸and R⁹ can be attached to one another and together form a cyclic ringhaving 3 to 8 C atoms which optionally contains, in addition tonitrogen, at least one further heteroatom selected from the groupconsisting of —S—, —O— and —NR⁶—, R⁴ is A, Ar, —Si(R⁶)₃, —Sn(R⁶)₃, —SR⁷,—OR⁷, —NR⁸R⁹ in which R⁸ and R⁹ are as defined above or R⁸ and R⁹ or tworadicals R⁴ can be attached to one another and together form a cyclicring having 3 C atoms R⁶, R⁷, R⁸ and R⁹ independently of one another areA or Ar, A is a straight-chain or branched alkyl radical having from 1to 10 C atoms, a straight-chain or branched alkenyl radical having 2 to10 C atoms, or a straight-chain or branched alkynyl radical having 2-10C atoms or a substituted or unsubstituted cycloalkyl radical having 3-8C atoms, or a mono- or polyunsaturated cycloalkyl radical having 3-8 Catoms, by carrying out the process in the presence of a catalyst system,comprising a metal dioxide selected from the group consisting oftitanium dioxide, and hafnium dioxide and a cocatalyst of the generalformula (IV), (V) M′^((s+)) (O-isopropyl)_(s)  (IV)R₃SiX  (V) in whichM′ is Al, Ca, Na, K, Si or Mg, s is an integer from 1 to 4 and is theoxidation state of the metal, R is alkyl having 1 to 10 C atoms or arylhaving 6 to 20 C atoms, X is F, Cl, Br, or CN, or the general formulae(CH₃)₂ClSi(CH₂)₂SiCl(CH₃)₂ (CH₃)₂ClSi(CH₂)₃CN [(CH₃)₃Si]₂O [(CH₃)₃Si]₂NHor [(CH₃)₃Si]₂.
 13. A process according to claim 4, wherein M¹ is Mg orNa.
 14. A process according to claim 12, wherein M¹ is Mg or Na.